Age-dependent changes in hepatocellular structure and function are currently being evaluated in the Fischer 344 male rat. Recently completed stereological studies demonstrated several important quantitative changes in hepatocyte fine structure as a function of animal age, including: (1) a net loss of smooth surfaced endoplasmic reticulum membrane; (2) a reduction in the volume of the mitochondrial compartment and (3) an increase in the volume of the dense body or lysosome compartment. In addition, most changes occurred between the young and mature and between the mature and senescent animals, creating remarkable similarities in hepatocyte ultrastructure between the young (1 month) and senescent (30 months) rats. Since much of the data concerning age-related changes in hepatic drug metabolism is somewhat confusing and conflicting, a comprehensive analysis of this liver function is currently in progress. Three separate inducible systems are being evaluated: (1) the hepatic mixed function oxidase system enzymes; (2) the smooth surfaced endoplasmic reticulum and (3) the hepatocellular autophagic response. This study involves a closely correlated structural and functional approach employing stereology and enzyme biochemistry. A number of drug-metabolizing enzymes (NADPH cytochrome-c reductase, ethylmorphine N-demethylase), cytochrome P450, and lysosomal enzymes (acid phophatase and beta-glucuronidase) are being measured in response to a strict schedule of drug administration and subsequent cessation of treatment. These biochemical/functional data are being correlated with the results obtained in a sophisticated stereological analysis of the hepatocellular autophagic response and the proliferation of the endoplasmic reticulum.